Update on bacterial meningitis: epidemiology, trials and genetic association studies

Bacterial meningitis is a life-threatening disease that continues to inflict a heavy toll. We reviewed recent advances in vaccination, randomized studies on treatment, and genetic association studies in bacterial meningitis. The incidence of bacterial meningitis has decreased after implementation of vaccines, and further implementation of existing conjugate vaccines particularly in low-income countries is expected to reduce the global disease burden. Several randomized studies have been performed recently in this field. Clinical studies showed that short duration (5 days) of antibiotic treatment is as effective as longer duration treatment in low-income countries, and that dexamethasone decreases death and neurological sequelae in high-income countries. Ongoing trials will further define the role of paracetamol, glycerol and hypothermia in bacterial meningitis. Genetic association studies identified pathophysiological mechanisms that could be counteracted in experimental meningitis, providing promising leads for future treatments. Conjugate vaccines have reduced the burden of bacterial meningitis in high-income countries, but implementation of available vaccines in low-income countries is necessary to reduce disease burden worldwide. Adjunctive dexamethasone therapy has beneficial effects in patients with bacterial meningitis but only in high-income countries. Genetic association studies may reveal targets for new treatment strategie

Hydrocephalus in adults with community-acquired bacterial meningitis

Objective: To evaluate the occurrence, treatment, and outcome of hydrocephalus complicating community-acquired bacterial meningitis in adults. Methods: Case series from a prospective nationwide cohort study from Dutch hospitals from 2006 to 2009. Results: Hydrocephalus was diagnosed in 26 of 577 episodes (5%) and was classified as communicating hydrocephalus in all but 1 patient. The majority of patients (69%) presented with hydrocephalus on admission. Most common causative bacteria were Streptococcus pneumoniae (in 14 patients, 54%) and Listeria monocytogenes (in 4 patients, 15%). Thirteen patients died (50%) and 18 had an unfavorable outcome (69%). Hydrocephalus was an independent predictor of death in a multivariate analysis (odds ratio 7.81, 95% confidence interval 2.91-20.8). Six patients underwent an intervention: 2 patients (8%) had serial lumbar punctures; 4 patients (15%) underwent external ventricular CSF catheter placement. Median time from diagnosis of hydrocephalus to CSF shunting was 12 hours (range 0-4 days). All patients who underwent CSF shunting died or had a poor outcome. Conclusions: Hydrocephalus complicates community-acquired bacterial meningitis in 5% of adult cases and is associated with high fatality rates. A minority of patients underwent neurosurgery and outcome was uniformly poor in these patients. Neurology (R) 2010;75: 918-92

Adjuvant treatment with dexamethasone plus anti-C5 antibodies improves outcome of experimental pneumococcal meningitis: a randomized controlled trial

We compared adjunctive treatment with placebo, dexamethasone, anti-C5 antibodies, and the combination of dexamethasone plus anti-C5 antibodies in experimental pneumococcal meningitis. In this prospective, investigator-blinded, randomized trial, 96 mice were infected intracisternally with 10(7) CFU/ml Streptococcus pneumoniae serotype 3, treated with intraperitoneal ceftriaxone at 20 h, and randomly assigned to intraperitoneal adjunctive treatment with placebo (saline), dexamethasone, anti-C5 antibodies, or dexamethasone plus anti-C5 antibodies. The primary outcome was survival during a 72-h observational period that was analyzed with the log-rank test. Secondary outcome was clinical severity, scored on a validated scale using a linear mixed model. Mortality rates were 16 of 16 mice (100%) in the placebo group, 12 of 15 mice (80%) in the dexamethasone group, 25 of 31 mice (80%) in the anti-C5 antibody group, and 18 of 30 mice (60%) in the dexamethasone plus anti-C5 antibody group (Fisher's exact test for overall difference, P = .012). Mortality of mice treated with dexamethasone plus anti-C5 antibodies was lower compared to the anti-C5 antibody-treated mice (log-rank P = .039) and dexamethasone-treated mice (log-rank P = .040). Clinical severity scores for the dexamethasone plus anti-C5 antibody-treated mice increased more slowly (0.199 points/h) as compared to the anti-C5 antibody-treated mice (0.243 points/h, P = .009) and dexamethasone-treated mice (0.249 points/h, P = .012). Modeling of severity data suggested an additive effect of dexamethasone and anti-C5 antibodies. Adjunctive treatment with dexamethasone plus anti-C5 antibodies improves survival in severe experimental meningitis caused by S. pneumoniae serotype 3, posing an important new treatment strategy for patients with pneumococcal meningiti

Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study

We studied causative pathogens, clinical characteristics, and outcome of adult community-acquired bacterial meningitis after the introduction of adjunctive dexamethasone treatment and nationwide implementation of paediatric conjugate vaccines. In this cohort study, we prospectively assessed adults (age >16 years) with community-acquired bacterial meningitis in the Netherlands, identified through the National Reference Laboratory for Bacterial Meningitis or individual physicians between Jan 1, 2006, and July 1, 2014. We identified independent predictors of an unfavourable outcome (Glasgow Outcome Scale score 1-4) by logistic regression. We assessed 1412 episodes of community-acquired bacterial meningitis. Incidence declined from 1·72 cases per 100,000 adults per year in 2007-08, to 0·94 per 100,000 per year in 2013-14. Streptococcus pneumoniae caused 1017 (72%) of 1412 episodes. Rates of adult bacterial meningitis decreased most sharply among pneumococcal serotypes included in paediatric conjugate vaccine, and in meningococcal meningitis. We found no evidence of serotype or serogroup replacement. The overall case fatality rate was 244 (17%) of 1412 episodes and unfavourable outcome occurred in 531 (38%) of 1412 episodes. Predictors of unfavourable outcome were advanced age, absence of otitis or sinusitis, alcoholism, tachycardia, lower score on the Glasgow Coma Scale, cranial nerve palsy, a cerebrospinal fluid white-cell count lower than 1000 cells per μL, a positive blood culture, and a high serum C-reactive protein concentration. Adjunctive dexamethasone was administered for 1234 (89%) of 1384 assessed episodes. The multivariable adjusted odds ratio of dexamethasone treatment for unfavourable outcome was 0·54 (95% CI 0·39-0·73). The incidence of adult bacterial meningitis has decreased substantially, which is partly explained by herd protection by paediatric conjugate vaccines. Adjunctive dexamethasone treatment was associated with substantially improved outcome. European Research Council, National Institute of Public Health and the Environment, European Union, Academic Medical Center, and Netherlands Organization for Health Research and Developmen

Complement factor H contributes to mortality in humans and mice with bacterial meningitis

Background: The complement system is a vital component of the inflammatory response occurring during bacterial meningitis. Blocking the complement system was shown to improve the outcome of experimental pneumococcal meningitis. Complement factor H (FH) is a complement regulatory protein inhibiting alternative pathway activation but is also exploited by the pneumococcus to prevent complement activation on its surface conferring serum resistance. Methods: In a nationwide prospective cohort study of 1009 episodes with community-acquired bacterial meningitis, we analyzed whether genetic variations in CFH influenced FH cerebrospinal fluid levels and/or disease severity. Subsequently, we analyzed the role of FH in our pneumococcal meningitis mouse model using FH knock-out (Cfh -/-) mice and wild-type (wt) mice. Finally, we tested whether adjuvant treatment with human FH (hFH) improved outcome in a randomized investigator blinded trial in a pneumococcal meningitis mouse model. Results: We found the major allele (G) of single nucleotide polymorphism in CFH (rs6677604) to be associated with low FH cerebrospinal fluid concentration and increased mortality. In patients and mice with bacterial meningitis, FH concentrations were elevated during disease and Cfh -/- mice with pneumococcal meningitis had increased mortality compared to wild-type mice due to C3 depletion. Adjuvant treatment of wild-type mice with purified human FH led to complement inhibition but also increased bacterial outgrowth which resulted in similar disease outcomes. Conclusion: Low FH levels contribute to mortality in pneumococcal meningitis but adjuvant treatment with FH at a clinically relevant time point is not beneficial

Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis

Background: Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the pro-inflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Methods: We investigated mannose-binding lectin-associated serine protease (MASP-2) levels in cerebrospinal fluid (CSF) samples derived from the diagnostic lumbar puncture, which was available for 307 of 792 pneumococcal meningitis episodes included in our prospective nationwide cohort study (39%), and the association between these levels and clinical outcome. Subsequently, we studied the role of MASP-2 in our experimental pneumococcal meningitis mouse model using Masp2 −/− mice and evaluated the potential of adjuvant treatment with MASP-2-specific monoclonal antibodies in wild-type (WT) mice. Results: MASP-2 levels in cerebrospinal fluid of patients with bacterial meningitis were correlated with poor functional outcome. Consistent with these human data, Masp2-deficient mice with pneumococcal meningitis had lower cytokine levels and increased survival compared to WT mice. Adjuvant treatment with MASP-2-specific monoclonal antibodies led to reduced complement activation and decreased disease severity. Conclusions: MASP-2 contributes to poor disease outcome in human and mice with pneumococcal meningitis. MASP-2-specific monoclonal antibodies can be used to attenuate the inflammatory response in pneumococcal meningitis